(a) Field of the Invention
The invention relates to a new delivery system for administering drugs, vaccines or other charged compounds. The present invention also relates to a new method for entrapping charged macromolecules.
(b) Description of Prior Art
In the field of vaccine, there is a growing interest for the development of colloidal delivery systems, similar to liposomes and nanoparticles, but capable of entrapping a fairly large amount of macromolecular proteins. Colloidal delivery systems must also meet the pharmaceutical requirements for product shelf life.
Several colloidal systems have been investigated to develop safer forms of drugs and vaccines. In general, the prime objective of these systems was to allow efficient delivery of pharmaceuticals to a biological site. In this context, macrophages have been identified as being a target for macromolecular proteins delivered by colloidal systems. However, it is well known that efficient delivery of a macromolecular protein to a biological site using colloidal delivery systems requires a stable entrapment of the macromolecular protein in the delivery system used.
According to studies evaluating entrapment of macromolecular protein in delivery systems, the major drawbacks limiting the use in various areas of pharmaceutical industries is a relatively low entrapment capacity of water-soluble macromolecular proteins. Water-soluble macromolecular proteins are poorly entrapped in colloidal systems because of their large size. Usually, the entrapment of large water-soluble macromolecular protein in liposomes depends on the nature of the aqueous phase, and rarely exceeds 50%.
There are several mechanisms suspected to be responsible for the water-soluble protein entrapment in colloidal systems. A general assumption is that water-soluble proteins are freely entrapped in the aqueous phase of the colloidal systems, like liposomes. The entrapment of a much larger water-soluble macromolecular protein is difficult to realize because of their large size. The introduction of giant liposomes and water-in-oil (w/o) emulsions has only partially remedied to the situation, because the efficiency of protein entrapment obtained using these systems does not reflect the actual capacity of the aqueous phase of these systems.
Furthermore, the methods used in the prior art to prepare delivery systems are in general time-consuming and often non-compatible with current pharmaceutical requirements.
As seen above, there is a great need for a delivery system capable of entrapping a broad range in size and a large amount of water-soluble proteins.
One aim of the present invention is to provide a method for entrapping water-soluble proteins using variable electrostatic interactions.
Another aim of the present invention is to provide a delivery system entrapping water-soluble proteins using variable electrostatic interactions.
Another aim of the present invention is to provide a delivery system prepared by a method already accepted in the pharmaceutical industry.
In accordance with the present invention, there is provided a biphasic delivery system for charged molecules comprising a negatively charged hydrophobic organic phase and a positively charged inorganic phase. The organic phase and the inorganic phase are adapted to entrap charged molecules by electrostatic bonds between the organic phase, the inorganic phase and the at least one charged molecule.
The organic phase is preferably an oil-in-water emulsion, which comprises a neutral oil and a negatively charged organic compound. Such neutral oil is, for example and without being limited thereto, selected from the group consisting of squalane, soybean oil, sesame oil and peanut oil. The negatively charged organic compound is preferably dicetylphosphate.
The inorganic phase of the delivery system of the present invention preferably comprises alum.
The delivery system preferably has a diameter of at most five micrometers when the charged molecules are entrapped therein.
Still in accordance with the present invention, there is provided the delivery system as described above, which further comprises charged molecules. The charged molecules may be for example DNA.
In accordance with the present invention, there is also provided a method for producing a delivery system as defined above. The method comprises the steps of contacting a negatively charged hydrophobic organic phase, charged molecules and a positively charged inorganic phase and mixing same for entrapping the charged molecules between the organic phase and the inorganic phase. Preferably, the negatively charged organic phase and the charged molecules are first mixed together, followed by addition and mixing of the positively charged inorganic phase therein.
The method of the present invention is simple and easily and reproducibly scaled up for industrial applicability. A well-defined and specific size distribution of the delivery system can be prepared with the present method. Hence, the system is another aspect of the present invention, which is meant to include a carrier for macromolecule, an adjuvant for vaccine, a slow-delivery system or a stabilizing agent.